Bone growth and mineralization are dependent on the activities of two cell types, osteoclasts and osteoblasts, although chondrocytes and cells of the vasculature also participate in critical aspects of these processes. Developmentally, bone formation occurs through two mechanisms, endochondral ossification and intramembranous ossification, with the former responsible for longitudinal bone formation and the later responsible for the formation of topologically flat bones, such as the bones of the skull. Endochondral ossification requires the sequential formation and degradation of cartilaginous structures in the growth plates that serve as templates for the formation of osteoblasts, osteoclasts, the vasculature and subsequent mineralization. During intramembranous ossification, bone is formed directly in the connective tissues. Both processes require the infiltration of osteoblasts and subsequent matrix deposition.
Chronic kidney disease is associated with a progressive deterioration in mineral homeostasis, with a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating hormones, such as parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, other vitamin D metabolites, fibroblast growth factor-23, and growth hormone. See, Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group, In: Kidney Int Suppl. (2009) 76 (Suppl 113):S1-130, page S3. The mineral and hormone homeostasis that is disrupted in chronic kidney disease is critical for initial bone formation during growth (bone modeling) and bone structure and function during adulthood (bone remodeling). As a result, bone abnormalities are found in patients with chronic kidney disease. In addition, similarly due to the disruption in mineral and endocrine functions, extraskeletal calcification may be found in patients with chronic kidney disease. These syndromes are termed chronic kidney disease-related mineral and bone disorders (“CDK-MBD”).
Bone undergoes continuous turnover. Bone turnover is the process of resorption followed by replacement of bone. Osteoblasts and osteoclasts are the cells necessary for bone turnover. Low turnover and adynamic bone diseases are characterized by reduced or absent resorption and replacement of bone. CKD-MBD can be characterized by low turnover or adynamic bone. (Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group, In: Kidney Int Suppl. (2009) 76 (Suppl 113):S1-130, page S34).
Increased calcium levels in the vasculature can lead to vascular calcification, a condition characterized by increased vessel stiffening. Patients with vascular calcification have an increased risk of myocardial infarction, and vascular calcification is particularly prevalent in patients suffering from kidney disease, e.g., CKD-MBD. See, e.g., Shanahan et al., 2011, Circ. Res. 109:697-711.
Two related type II receptors, ActRIIA and ActRIIB, have been identified as the type II receptors for activins (Mathews and Vale, 1991, Cell 65:973-982; Attisano et al., 1992, Cell 68: 97-108). Besides activins, ActRIIA and ActRIIB can biochemically interact with several other TGF-beta family proteins, including BMP7, Nodal, GDF8, and GDF11 (Yamashita et al., 1995, J. Cell Biol. 130:217-226; Lee and McPherron, 2001, Proc. Natl. Acad. Sci. 98:9306-9311; Yeo and Whitman, 2001, Mol. Cell 7: 949-957; Oh et al., 2002, Genes Dev. 16:2749-54). ALK4 is the primary type I receptor for activins, particularly for activin A, and ALK-7 may serve as a receptor for activins as well, particularly for activin B.